The present invention relates to preparations for veterinary medicine, which contain a combination of 1-[4-chloro-3-(3-chloro-5-trifluoromethyl-2-pyridyloxy)phenyl]-3-(2,6-difluorobenzoyl)urea [hereinafter compound (B)] and a further active ingredient of formula (i) below from the avermectin class. It also relates to the use of these two components in the production of veterinary preparations and their joint usage in a method of controlling ecto- and endo-parasites on productive livestock, domestic animals and pets.
1-[4-chloro-3-(3-chloro-5-trifluoromethyl-2-pyridyloxy)phenyl]-3-(2,6-difluorobenzoyl) including the preparation thereof, is known from European Published Specification EP-0.079,311. This compound has in the following the name xe2x80x9ccompound Bxe2x80x9d.
In the context of the invention, the active ingredient from the avermectin class is a macro-cyclic compound of formula (i) 
wherein
R1 is hydrogen or one of radicals 
R2 is xe2x80x94CH(CH3)xe2x80x94CH3, xe2x80x94CH(CH3)xe2x80x94C2H5, xe2x80x94C(CH3)xe2x95x90CHxe2x80x94CH(CH3)2 or cyclohexyl; R3 is hydrogen or hydroxy if the bond between atoms 22 and 23 represents a double bond, or is hydrogen or the group xe2x95x90Nxe2x80x94Oxe2x80x94CH3 if a single bond is present between atoms 22 and 23; and R4 is HOxe2x80x94 or HOxe2x80x94Nxe2x95x90, in free form or in the form of a physiologically acceptable salt.
Typical representatives of compounds of formula (i) are:
1) Ivermectin is a mixture of two compounds of formula (i), wherein R1 is the radical 
and R3 is hydrogen steht, whereby atoms 22 and 23 are linked by a single bond and R2 is either xe2x80x94CH(CH3)xe2x80x94CH3 or xe2x80x94CH(CH3)xe2x80x94C2H5; both of them, including their preparation, are known from EP-0,001,689. Ivermectin is preferred in the context of the present invention.
2) Doramectin is a compound of formula (i), wherein R1 is the radical 
and R3 is hydrogen, whereby atoms 22 and 23 are linked by a double bond and R2 is cyclohexyl. Doramectin is described e.g. in EP-0,214,731 and EP-0,276,131.
3) Moxidectin, also known as LL-F28249xcex1 is a compound of formula (i), wherein R1 and R3 are hydrogen, whereby atoms 22 and 23 are linked by a single bond and R2 signifies xe2x80x94C(CH3)xe2x95x90CHxe2x80x94CH(CH3)2. Moxidectin is known from U.S. Pat. No. 4,916,154.
4) Selamectin is 25-cyclohexyl-25-de(1-methylpropyl)-5-deoxy-22,23-dihydro-5-(hydroxyimino)avermectin B1 monosaccharide and thus a compound of formula (i), wherein R1 is the radical 
R2 signifies cyclohexyl, R3 is hydrogen, whereby atoms 22 and 23 are linked by a single bond and R4 is HOxe2x80x94Nxe2x95x90. Selamectin is known e.g. from: ECTOPARASITE ACTIVITY OF SELAMECTIN; A novel endectocide for dogs and cats. A Pfizer Symposium, held in conjunction with The 17th international Conference of the World Association for the Advancement of Veterinary Parasitology, Aug. 19, 1999. Copenhagen, Denmark.
The compounds of formula (i) are known from the said publications or are obtainable analogously to known agents.
As is known, the life cycles of the different parasites, which can infest humans or animals, are very complex, which makes it difficult to control them in many cases. In addition, multiple diseases are often a problem that has not yet been satisfactorily resolved. In particular in warmer regions, herd animals such as cattle and sheep, are often infected by an epidemic of helminths and other worm diseases. These diseases in themselves are frequently life-threatening. In many ways, these animals which are already weakened by the endoparasites are additionally infested by ectoparasites, in particular ticks, which often appear en mass and further weaken these animals and form an additional stress factor. The animals which are already weakened by the worms take up even less nourishment because of these plagues, lose weight even more rapidly and require intensive treatment and attention. Moreover, ticks may be infected with various kinds of pathogens, and transmit them particularly easily to host animals that are already weakened and whose immune system is also weakened. There is therefore a vital need to provide preparations which successfully eliminate both the parasitic worms and ticks.
Typical helminthic diseases in the context of the present invention are those caused by members of the nematode class. These include for example the families Filariidae and Setariidae, and the genera Haemonchus, Trichostrongylus, Ostertagia, Nematodirus, Cooperia, Ascaris, Bunostumum, Oesophagostonum, Chabertia, Trichuris, especially Trichuris vulpis, Strongylus, Trichonema, Dictyocaulus, Capillaria, Strongyloides, Heterakis, Toxocara, especially Toxocara canis, Acaridia, Oxyuris, Ancylostoma, especially Ancylostoma caninum, Uncinaria, Toxascaris and Parascaris; Dirofilaria, especially Dirofilaria immitis (heartworm).
Ticks can feed exclusively from the blood of one host or also from the blood of different hosts. The attach themselves firmly to the host animal and suck its blood. The fully engorged females drop from the host animal and then lay a large number of eggs in a suitable niche in their surroundings. The developing larvae then search for a new host animal in order to develop into adults via the nymph stage, and in turn fully engorge themselves with blood. Certain species feed on two and some on three host animals during their lifecycle.
Ticks of importance in this instance are above all those which belong to the genera Amblyomma, Boophilus, Hyalomma, Ixodes, Rhipicephalus and Dermacentor, especially the species Boophilus microplus and B. annulatus, and most especially B. microplus. They are responsible for the transmission of numerous diseases which can affect humans and animals. The diseases which are mostly transmitted are bacterial, protozoan, rickettsial and viral. The pathogens of such diseases are transmitted especially by ticks which feed on more than one host. These diseases can lead to the debilitation or even death of the host animals. In most cases they cause considerable economic damage, for example by diminishing the value of meat from livestock, damaging the usable skin, or reducing milk production.
Ticks of the above species are traditionally controlled on otherwise healthy host animals by treating the infested animals with an acaricidally active composition depending on the type of infestation involved, i.e. by curative means. The occurrence of ticks, for example on pasture land, is heavily dependent, however, on seasonal weather conditions, and the ultimate infestation of the host animals itself depends also on their resistance to the ticks. This means that preventative control of the ticks is difficult and time-consuming, since inter alia the severity of infestation by the pests can only be estimated with difficulty. In the case of animals that have already been weakened by other parasites, e.g. the above-mentioned worms, effective control of the ticks is particularly important. Here, preparations are preferred, which show marked contact action, i.e. either kill the ticks upon contact with the pelt or skin, or induce them not to attach themselves and suck blood. With weakened animals, it is especially important that they are not additionally stressed by the anti-tick treatment, and that they are not treated with a number of veterinary preparations, the side effects of which might accumulate. Mass-produced, suitably-adapted, well-tolerated broad-band preparations might provide a remedy.
It is becoming increasingly difficult to synthesise or to isolate from natural sources new classes of active ingredient, which are equal to the active substances already available or even superior to them. Many of the known active ingredients in the field of animal health show exceptionally marked activity against certain target parasites. Unfortunately, their activity is usually restricted either to external or internal parasites only, or they have substantial gaps in their spectrum of activity in one respect or another. For treatment of already weakened animals, however, it would be desirable to provide broad-band preparations, which cover a broad spectrum of activity, are very well tolerated and can reduce the number of treatments to a minimum.
Instead of searching for new active ingredients, possibly for years without success, It may be preferable to attempt to achieve the desired broad-band effect by combining known active substances. At first appearance, this seems to be a simple task, since the spectra of activity of different classes of substances have been known for a long time. In reality however, the mere combination of two active substances seldom leads to the desired success, since the simultaneous administration of different active substances can lead to unpredictable kinetic and metabolic effects, not to mention potentiation of the undesired side effects. Also, contrary potentiating or diminishing effects are observed, and even undesired chemical reactions between the degradation products arising through the endogenous enzymes. Not all of the proposed combinations exhibit the desired broad-band spectrum upon practical application. In many cases, new deficiencies in efficacy occur, which render the preparation useless for the planned application or restrict it to specific cases, since one or other of the frequently appearing parasites is not covered or is unsufficiently covered, or the immune system of the treated animals is adversely affected, and they become susceptible to e.g. fungal diseases or other secondary infections, which makes their treatment more difficult and involves the usage of further veterinary preparations. A further difficulty is that helminthic infestations may be controlled particularly effectively if the corresponding preparations are administered systemically, i.e. either percutaneously or orally, and reach the parasites via the blood stream. On the other hand, tick preparations are preferably administered topically, i.e. to the skin or the pelt of the host animal, and exhibit their anti-tick activity there by contact. It is a difficult undertaking to find active ingredients that are to act in both treatments and which may be applied either systemically or topically or in both ways.
If e.g. helminthic diseases and tick infestation are to be treated simultaneously, proposals for combination preparations have already been made in literature:
In WO 96/25852 for example, there is an overall proposal to use the combination of a benzoylurea with a further active ingredient from the series milbemycin, avermectin, milbemycinoxim, moxidectin, ivermectin, abamectin and doramectin. However, only the combinations lufenuron and milbemycin and fluazuron and milbemycin are mentioned specifically. There is no indication of using a specific combination of a benzoylurea with a macrocyclic compound, as used in the present invention. Furthermore, in European published specification EP-0,242,502, the combination of avermectinen with a further active ingredient from the class of phorphoric acid esters, carbamates, carboxylic acid esters, certain benzoylureas or other known insecticides or acaricides, is proposed for the simultaneous control of insects, acarids and nematodes, albeit in the field of plant protection. This specification specifically proposes e.g. chlorfluazuron (compound IIb, page 3) as the benzoylurea component. This has a certain structural closeness to the fluazuron used according to the invention
If now an attempt is made to transfer these experiences from plant protection to usage in the field of veterinary medicine, which is the subject of the present invention, it is quickly established that the spectrum of activity of the proposed combinations has considerable deficiencies as regards the ectoparasites. Although the avermectin portion does lead to very good efficacy against various nematodes, the addition of the proposed benzoylureas does not gove the desired activity in the field of ectoparasites, especially against the most important members of the acarid order (mites and in particular ticks).
It has now surprisingly been found that a relatively slight structural modification to the chlorfluazuron proposed in EP-0,242,502 not only balances out this deficit in activity, but also leads to extremely well tolerated preparations which act rapidly and persistently against various helminthic diseases and against ticks and mites, and in this way are eminently suitable for usage in the field of animal health. In addition, administration to cattle and sheep shows that these new combination preparations do not have an adverse effect on the normal behaviour of the animals among one another, nor in their eating habits. The new combinations may therefore be used not only curatively, but also preventatively and also over longer periods of time when there is an increased risk of infestation, without the appearance of negative side effects which would harm the animals.
The benzoylureas proposed in EP-0,242,502 are notable structurally for the para-phenoxy- or para-pyridyloxyphenyl group. One notable benzoylurea is e.g. the following substance (A) [in EP-0,242,502=substance IIb, page 3]: 
By combining this substance (A) with typical representatives of avermectin derivatives, it is established in the case of the combination with ivermectin, doramectin and moxidectin that they are not suitable for usage in animal health, since although they eliminate the parasitic worms rapidly and persistently, they clearly have no influence on ticks.
By comparing the biological activity of these combinations depicted in the prior art with that of the proposed combinations, which contain as the first component of the mixture likewise ivermectin, doramectin or moxidectin and as the second component the following benzoylurea (B): 
it is established that by using this structural isomer (B), in which also one chlorine atom is missing, a significantly broader spectrum of activity is attained, which is important for veterinary medicine. As well as the frequently appearing worms, it also covers mites and in particular ticks, and when administered at dosages which are effective against the target parasites, it does not create any undesired side effects. In addition, it is surprisingly established that the combinations according to the invention may be administered systemically and topically.